Abstract Genetic mutations play an important role in human aging and disease. By changing our genetic code, a mutation can disrupt the activity of a protein and permanently change the physiology of our cells. As a result, mutations can have a profound effect on human health. For instance, mutations in the germ line can result in congenital disorders, whereas somatic mutations contribute to cancer, muscle wasting and neuronal degeneration. An exciting new set of experiments now suggests that genetic mutations are not the only errors that contribute to human disease. In this research proposal, I will test the hypothesis that non-genetic mutations, i.e. mutations that occur during transcription and translation, also contribute to aging and age- related disease. To do this, I am developing highly sensitive technology that is capable of detecting these errors in vivo and I will use this tool to identify the parameters that modulate their error rates. Through genetic engineering I am also directly altering the error rate of transcription and translation to test whether this impacts cellular aging and age-related pathology. Finally, I will determine the molecular mechanisms by which non- genetic mutations impact cellular function, and identify the cellular pathways that are in place to prevent dysfunction. Together, these experiments may significantly deepen our understanding of aging and age-related pathology and help identify new targets for treatments or prevention strategies in the clinic.